Group 4 MMCKate, James, Lee, Quaderi, Jeeves, Satwik, Helen, Shravya, Jo, Nikhil

Paper PBL 15 – Extreme Lethargy

Case HistoryMr Josh Felix25 years old, roadie for a “grunge band”Grew up in Wagga Wagga, moved to Glen

Waverley 5 years agoPresenting Complaint:6 week history of increasing lethargy,

productive cough, weight loss he assumed it was exacerbation of asthma

• Assuming it was asthma, he attended 24 hour medical clinic for repeat prescription of asthma medications given salmeterol, fluticasone inhalers, prednisolone 5mg and amoxycillin 500mg for his cough.

• Returned 5 days later due to worsening symptoms. New doctor on duty takes thorough history and examination to find…

Josh’s HistoryProductive cough – sputum thick, light brown,

coughing one “table spoon” each morningNo haemoptysisMild dyspnoea on exertionNo chest painFever; chills & muscle aches followed by profuse

sweatingAsthma since age 5; 3-4 attacks each year; uses

inhalers intermittentlyNo other medicationsSmokes 25 cigarettes per day, done so for 7 yearsNon-IVDU; Alcohol: 4 drinks per day + 2-3 binges

per month

Further Relevant HistoryFHx – Josh’s mother was treated for “spitting

blood” 18 years ago. Brother has severe asthma.Contact Hx – members of band have a “cold”Sexual Hx – many different female partners, often

unprotected. Sex with a man once.Travel Hx – Never travelled overseas. Recently

spent 2 months in Darwin.Animal contact – none of relevanceImmunisations – can’t be recalledDietary Hx – erratic diet, mainly junk food, no

fresh fruit or vegetables

Physical Examination• Gaunt, white male; not acutely ill.• Pulse 98/min• BP 130/74 mmHg• RR 16/min• Oral temp 37.6°C• Weight 58kg• Hyperexpanded chest, soft rhonchi bilaterally,

no other focal resp signs• CVS normal, no hepatomegaly• Additional notes of tattoos, multiple piercings,

cigarette pack in t-shirt sleeve and no BCG scar

Initial Investigation ResultsFBE: Hb 109g/L, WBC 14.5x10^9/L, platelets

140x10^9/LHIV serology: negativeLFT’s:

bilirubin 19 (N<17) ALP 110 (N<120) ALT 240 (N<56) GGT 150 (N<75) Albumin 26 g/L (N35-45)

CXR: hyperexpanded lung fields, right apex opacity with 2x2cm cavity, no cardiomegaly, hilar regions normal

Sputum Gram stain: WBC +++, mixed Pos and Neg organisms

Sputum Culture: normal oral floraSpecial Cultures:

Burkholderia pseudomallei: pending AFB stain: positive ++ (first specimen) AFB culture: in progress

Differential Diagnosis• Country of birth: Australia

• Productive cough – sputum thick, light brown, coughing one “table spoon” each morning

• Mild dsypnoea on exertion• Fever; chills & muscle aches followed by

profuse sweating• Symptoms progressively worse over 6 weeks

with weight loss• FHx – Josh’s mother was treated for “spitting

blood” 18 years ago. • Sexual Hx – many different female partners,

often unprotected. Sex with a man on once.• Travel Hx – nil overseas, 2 months in Darwin.• Immunisations – can’t be recalled, no HBG scar• 7 pack years smoking, high alcohol intake,

poor nutrition• Gaunt, white male; not acutely ill, weight 58kg• Hyperexpanded chest, soft rhonchi bilaterally,

no other focal resp signs• LFT’s: intrahepatic pattern with GGT • CXR: hyperexpanded lung fields, right apex

opacity with 2x2cm cavity, no cardiomegaly, hilar regions normal

• Sputum AFB stain: positive ++

Summary of Findings

•Tuberculosis•Pneumonia/Atypical Pneumonia

•Asthma exacerbation•COPD

•Bronchiectasis•Lung carcinoma

•HIV•Lung abscess

•Influenza

Risk Factors• Lowered immunity

– HIV, diabetes, ESRD, certain neoplasms (lung, lymphoma)

– Corticosteroids, transplant drugs– Age– Substance abuse

• Silicosis• Ethnicity

– Sub-saharan Africa– Mexico, the Phillipines, India and Vietnam

Risk FactorsClose contact with someone with TBTravelInfected with TB bacilli

Which risk factors does he have?

Epidemiology – World WideNo. 1 infectious disease problem> 2 billion people are infected with TB

bacilli9.4 million new cases (2008)1.8 million people died (2008)

500,000 had HIV

Epidemiology – World WideSouth-east Asia

Highest incidence and deathsApprox 3.2 million new cases (2008)

Sub-Saharan AfricaHighest incidence rate and mortality

rateApprox 2.8 million new cases (2008)

Epidemiology - Australia

Epidemiology - Australia

The PathogensTB is mainly caused by Mycobacterium

tuberculosis. Can occasionally be caused by M. bovis or M.

africanum. M. tuberculosis divides every 15-20 hours.It has a thick cell wall rich in lipids which

prevents it taking up most stains and helps it resist digestion in macrophages.

It is an aerobe & an acid fast bacillus.

Infection & DormancyM. tuberculosis is spread in aerosols released by

coughing/sneezing. It needs to be inhaled for infection to occur.

Once inhaled, the bacteria reach the alveoli and are phagocytosed by the alveolar macrophages. Their lipid coating and ability to inhibit phagosome-lysosome fusion enables them to avoid digestion.

This primary infection site is called a Ghon focus and is usually in the lower part of the upper lobe or the upper part of the lower lobe.

The bacteria soon reach the lymph nodes at the hilum of the lung. The Ghon focus and the infected node constitute a Ghon complex. These are visible on X ray.

Infection & Dormancy ctd.• The cell mediated immune reaction causes the

formation of granulomas.• These are composed of numerous leukocytes

surrounding a core of infected macrophages.• Most of the bacteria are destroyed but some enter

a dormant state and survive by slowing down their metabolism.

• Cells in the centre of the granulomas undergo necrosis. The resulting dead matter looks pale and cheesy and is called caseous necrosis.

• Some granulomas undergo calcification and can be seen on X-rays after the disease ceases to be active.

ReactivationThe primary infection may not be self

limiting if the host is very young/old or immunocompromised.

When the immune system is compromised in someone with latent TB (eg- HIV, diabetes, steroids) the M. tuberculosis can reactivate and cause secondary TB.Unlike the primary infection this is not self

limiting. The bacteria can spread to many parts of

the body and cause serious illness- eg: GIT, brain, liver

I(x) Active TB FBE• ↑ WCC (Infection)• ↓ Hb (Anaemia of chronic disease) U&E’s • (baseline) LFT’s • (baseline) ESR/CRP • (inflammation/infection) CXR HIV serology Sputum culture Blood gas Septic screen

I(x) Active PTBDiagnostic

Chest X-Ray Abnormal CXR often found with no symptoms but reverse extremely

rare PTB is unlikely in absence of radiographic abnormalities Exception is miliary TB or non-respiratory TBFindings Patchy or nodular shadows in the upper zones Loss of volume and fibrosis (with or without cavitation) Calcification may be presentSimilar CXR findings Histoplasmosis, fungal infections (cryptococcosis, coccidiomycosis,

blastomycosis, aspergillosis), bronchial carcinoma, cavitating pulmonary Infarcts

EVERY EFFORT MUST BE MADE TO OBTAIN MICROBIOLOGICAL EVIDENCE

A cavity is a walled hollow structure within the lungs. Diagnosis is aided by noting:wall thickness wall outline

changes in the surrounding lung

I(x) Active TBCulture Clinical Samples Sputum, pleura & pleural fluid,

urine, pus, ascites, bone marrow, CSF

Induce if non-productive (bronchoscopy & lavage)

Prolonged culture – 12wks

AFB – acid fast bacilli Ziehl-Neelsen stain Acid fast bacilli are stained

bright red and stand out against a blue background

Resistant to de-colouring when

washed with acid

I(x) Active TBOtherImaging for non-respiratory TB (CT, XR etc)PCR – rapid identification of

sensitivity/resistance (rifampicin)Biopsies – pleura, lymph nodes, solid lesions

etc

I(x) Latent TBWhen infected with M Tuberculosis, but do not have

active tuberculosis diseasePatients are not infectious. TB infections in Australia are predominantly due to

latent reactivationSimply put, the immune system ‘walls off’ the TB

bacilli (in a granulomatous lesion), which can lie dormant for years. It is kept in this state by the cell-mediated immune

system.Main Risk: around 10% of these people will develop

active TB during some point in their livesThe greatest risk being within the first 2 years of being

infected. Usually when their immune system is weakened.

Investigations – Mantoux Test (tuberculin skin test TST)Works via a hypersensitivity reaction by the cell-

mediated immune system to purified proteins from M. Tuberculosis (called Tuberculin).

Tuberculin is injected intradermally in the forearm and the resulting area of induration (not erythema) is measured 48-72 hours later.

Positive result is based on the size of the indurationPrevious vaccination with BCG may give false

positives.Mantoux test should be done to identify people with

an increased risk of TB, who would benefit from treating the latent infection. People with HIV, recent contacts of a person known to

have clinically active TB, health care workers at increased risk, etc.

Investigations – QuantiFERON-TB Assay A recently produced blood test that is able to

measure quantitatively the production of cytokine Interferon-γ by lymphocytes sensitised to mycobacterial proteins using an ELISA technique.

Advantages:Involves only 1 visit for a blood sample.No injection technique/subjective interpretation

problemsDoes not boost responses measured by subsequent

tests, which can happen with tuberculin skin testsIs not affected by prior BCG vaccination.

Clinical Manifestations of TBPulmonary disease

Primary disease Occurs soon after the initial infection in areas of

high TB transmission, often in children.Generally spreads to the upper zones of the lungLesion is peripheral with lymphadenopathy.Usually heals spontaneouslyBUT in children and immunocompromised people,

the primary site may rapidly enlarge causing central necrosis and cavitation

Presents generally with fever, malaise, cough, weight loss and haemoptysis.

There may also be a small pleural effusion Erythema nodosum due to hypersensitivity reaction

to the infective process.

Clinical Manifestations of TBPulmonary disease

Post-primaryAlso known as reactivation TB, this results from

endogenous reactivation of latent TB.This also favours the upper zones.Gradual onset of symptoms over weeks to months. Presents with lethargy, malaise, anorexia and loss of

weight with a fever and couch.Sputum may be mucoid, purulent or blood-stained.

A pleural effusion or pneumonia may be the presenting feature.

On examination, finger clubbing may be present in advanced disease. Often there are no physical signs in the chest though occasionally persistent crackles can be heard.

Signs of pleural effusion, pneumonia and fibrosis may be seen.

Clinical Manifestations of TB Extrapulmonary disease

Miliary or Disseminated Tuberculosis Due to haematogenous spread of bacteria and can be due to

either primary infection or reactivation. Nonspecific signs such as fever, night sweats, anorexia,

weakness and weight loss present. Eventually liver and spleen enlarge and tubercle lesions will

appear Tuberculous meningitis

Seen most often in children or immunocompromised adults. Results from haematogenous spread of pulmonary disease. May present with headache and slight mental changes, weeks

of low-grade fever, anorexia, malaise, anorexia and irritability.

May evolve acutely with severe headache, confusion, lethargy, altered sensation and neck rigidity.

Diagnosed via LP and if unrecognised it can be fatal.

Clinical Manifestations of TB• Extrapulmonary disease

– Cardiac • Pericarditis and pericardial effusions• This can lead to constrictive pericarditis due to fibrosis and

calcification an can be fatal.– Eyes

• Choroiditis– Genitourinary

• Pyuria and haematuria, flank pain, frequency, dysuria, nocturia– GIT

• Peritoneal TB causing abdominal pain and GI upset (AFB in ascites).

– Skeletal • Vertebral collapse, septic arthritis and osteomyelitis

– Skin • Jelly-like nodular rash (lupus vulgaris) and possible erythema

nodosum due to hypersensitivity reaction to infection

TreatmentHospitalisation:

Ill, smear positive, highly infectious patientsEsp. in multi-drug resistant TB

Continuous self-admin. of drugs for 6 months vital for successful RxLack of compliance 5% pts unresponsive to RxResistance to anti-TB drugs increasing:

Isoniazid resistance 4-6%Multidrug resistance 1%

Before treatment:Test FBC, liver, and renal function

Need to alter dosages in pts with liver/renal failureTest colour vision & acuity

Ethambutanol can cause (reversible) ocular toxicity

Treatment6 months

Rifampicin 600-900 mg, dailyIsoniazid 300 mg dailyPyrazinamide 2.5g, 3/week

First 2 monthsEthambutanol 30 mg/kg 3/week

First 2 monthsLonger regimen:

Bone TB (9 months)Tuberculosis meningitis (1yr)

NEVER use monotherapy Except when using Isoniazid for latent TB Rx

DOTS: Directly Observed Therapy (short-course)WHO incentive, to improve detection and complianceDOT plan: treating physician/TB nurseBi-weekly, thrice-weekly treatment instead of daily

Side EffectsRifampicin:

HepatitisSmall rise in AST acceptableStop if bilirubin rises

Orange discolouration of urine & tearsInactivation of the OCP

IsoniazidHepatitisNeuropathyPyridoxine deficitAgranulocytosis

EthambutanolOptic neuritis (colour vision first to deteriorate)

PyrazinamideHepatitisAthralgia (CI: gout, prophyria)

Follow-UpPatients should be seen regularly for

duration of chemotherapyOnce more after 3 months to check for

relapseChemoprophylaxis:

Pts with x-ray changes compatible with TB, but about to undergo immunosuppresive long-term Rx (ie dialysis)

Isoniazid 300-450 mg/day

Drug ResistanceMono-resistant TB – resistant to only one drugPoly-resistant TB – resistant to more than one drug but not the combination of isoniazid and rifampicin.Multidrug-resistant TB (MDR-TB)•TB caused by bacteria resistant to at least isoniazid and rifampicin. Extensively drug-resistant TB (XDR-TB)•TB caused by bacteria resistant to isoniazid and rifampicin (i.e. MDR-TB) plus any fluoroquinolone and any second-line anti-TB injectable drugs (amikacin, kanamycin or capreomycin)

There is an estimated 150 000 deaths per year from MDR-TB alone.

• Result from either primary infection with resistant bacteria or may develop secondarily in the course of treatment due to inadequate treatment regimens or poor compliance.

• Risk factors include – 1. Previous treatment for TB especially if prolonged2. Contact with a patient known to have drug resistant

TB or live in an area with high drug-resistant TB prevalence

3. Immunocompromised (HIV in particular)4. Poor compliance5. Culture +ve after 2 months treatment

• Can take up to 2 years to treat with drugs less potent, more toxic and more expensive. Higher mortality rate.

• Treatment is based on sensitivity testing with at least 3 drugs and an initial bactericidal injectable agent.

• Fluoroquinolone should be used where possible.

• XDR-TB Linezolid becomes mainstay treatment. Surgery is a limited option if disease localised.

Resistance Alternative

INH, RIF LEVO, PZA, EMB, AMK

INH, RIF, EMB LEVO, PZA, AMK, CS +/- PAS/ETH

INH, RIF, PZA LEVO, EMB, AMK, CS +/- PAS/ETH

INH, RIF, PZA, EMB LEVO, AMK, CS, PAS/ETH, +/- one more drug

First Line Drug Cross-resistance

INH Ethionamide

RIF All Rifamycins

PZA and EMB None

PreventionBacille Calmette Guerin (BCG) Vaccine

Live attenuated strain of Mycobacterium bovis; 1921

EfficacyClinical trials UK: protective effect of 60 to 80%;

Trials elsewhere have shown variable results; efficacy the closer one gets to the equator

Meta-analysis Colditz et al. (1994) = 50 per cent effective Most important protective benefits are in minimising the risk of

death, meningitis and miliary disease in neonates and young children

WHO recommend given to all children in countries highly endemic for TB

Australian Recommendations: 1. Aboriginal neonates in areas of high incidence (e.g. NT, Far North Queensland, N WA & SA)2. Individuals travelling to or living in areas with prevalence of TB3. Neonates born to parents with leprosy or a Fx of leprosy;4. HCWs who may be at high risk of exposure to drug resistant cases

Very safeAnaphylactoid reactions (rare); Most common is

development of a localised abscess at the site of injection, especially if the vaccination is given too deeply

Immuno-compromised risk for disseminated BCG infection

Scarring

C/I: Positive TST of greater than 5-mm diameter in duration; Immunocompromised (HIV, corticosteroids, chemo, malignancies); Pregnant (?); PHx TB; Febrile; Pt suffers from a generalised skin disease such as eczema and psoriasis

MethodTuberculin skin test (Mantoux) is done first (except

infants below 6 months where Hx of TB excluded)C/I if reactive - risk of severe local inflammation and

scarringSingle intradermal injection at the insertion of the

deltoid – other sites: risk of keloid formation

Infection ControlIsolation = Negative Pressure Rooms – prevent

cross-contaminations from room to roomGenerates negative pressure to allow air to flow into

the isolation room but not escape from the roomEducate patient about transmission cover

mouth when coughing etc

Prophylaxis• Screen close contacts with tuberculin test

+CXR– Tuberculin +ve, CXR –ve: nothing further– Pt with HIV, no BCG - isoniazid prophylaxis

↓risk by 40%– Child with +ve tuberculin test treatment– Tuberculin –ve in children/young adults

repeat in 6 wks; administer BCG if still –ve / treatment if +ve

– Children <1y with family member with TB isoniazid 6/12 + BCG with strain resistant to isoniazid

HIV and TBWorldwide TB is the most important opportunistic

infection in HIV patients – its the commonest killer.Around 20 million people worldwide are co

infected with HIV and TB. Dual infection of HIV and TB is very low in Australia

(sub Saharan Africa > 70%). < 5% of AIDS patients in Australia develop active TB.

1-7% of the HIV infected people with latent TB, will go on to develop active TB each year – a risk that is 4-25x higher than in non-HIV patients.

TB affects the course of HIV infection: in vitro cytokines released because of Mycoplasma TB enhances HIV replication.

Clinical manifestation depends on: CD4 status (level of

immunosuppresion) Whether the TB is from recently

acquired TB or from a reactivation of latent TB.

HIV patients with preserved CD4 counts usually present with pulmonary TB.

Atypical manifestations, extra pulmonary or disseminated TB are more common in: HIV patients with primary TB Those with reactivated TB Impaired immunity ( CD4 count

< 200 per microlitre)

Characteristic Late HIV infection *

Early HIV infection

Pulmonary : extra pulmonary disease

50:50 80:20

Chest radiograph

Intrathoracic lymphadenopathy

Common Rare

Lower lobe involvement

Common Rare

Cavitation Rare Common

Tuberculin response Rare Common

Sputum smear positivity

Less common Common

Adverse drug reactions

Common Rare

Relapse after treatment

Common Rare

Tuberculin skin test should be part of the routine tests of every newly diagnosed HIV infection – test for latent TB

All newly diagnosed patients with TB should be asked for HIV risk factors, and tested for HIV

A Mantoux rxn of > 5mm indicates TB in people with HIV

Occasionally patients with pulmonary TB can have normal CXR - unusual

Diagnosis can be tricky particularly in advanced HIV

Mycobacterium culture is most useful in Dx in such cases

Diagnosis (HIV + TB)

Treatment is complexRifampicin has pharmacokinetic interactions with

protease inhibitors (PI) – via hepatic cytochrome p450

There are also overlapping toxicities between HAART and anti-TB drugs: in particular hepatotoxicity, peripheral neuropathy and GI side effects.

In HIV patients not on HAART, standard TB therapy is good.

Treatment for HIV-associated TB

Josh’s progress…Admitted to hospital after coughing up blood all over

the band’s lead singer at the new album launchNext two sputum cultures are also positive, and Josh

is diagnosed with TBTB cultures also come back positive; confirmed by

PCR; sent for TB drug susceptibility testingJosh is placed in an isolated room; started on 4 anti-

TB drugs (rifampicin, isoniazid, pyrazinamide and ethambutol : “RIPE” drugs

Referred to allied health social work and dietitian after nursing staff find a bottle of bourbon smuggled in bedside locker

Responds well to anti-TB medication and lives happily ever after.

What do all of these people have in common...

John Keats – english poet. 2009 movie Bright Star with Abbie Cornish.

Singer Tom Jones, of “Sex Bomb” fame. Had TB at age 12

Singer Cat Stevens (Yusuf Islam) was close to death with TB in 1969.

Nicole Kidman’s character Satine, died from TB in Moulin Rouge

...they’ve all had tuberculosis